Various diagnostic imaging methods, such as X-ray CT (computed tomography), ultrasound imaging, MRI (magnetic resonance imaging) diagnosis, scintigraphy, etc. now exist. MRI is particularly advantageous because it can produce, without fear of exposure, cross-sectional images of body parts such as the brain, spinal cord, etc., where imaging by X-ray CT is often very difficult.
With MRI diagnosis, images are synthesized by computer based on signal data from hydrogen nuclei in the body so as to examine the condition of organs. Accordingly, MRI diagnosis is performed using paramagnetic metal ions having properties that shorten the relaxation time by interacting with nearby hydrogen nuclei. Among such metal ions, Gd3+ is particularly excellent in terms of the above-described properties, and increases the intensity of the signals in T1 weighted images. However, metal ions such as Gd3+ and the like are highly toxic, and therefore are stabilized by being bonded to a chelating ligand before being used as contrast agents for MRI.
Conventionally, diethylenetriamine pentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) and the like, which have an affinity with Gd3+, have been used as the chelating agent.
For example, Patent Document 1 discloses a contrast agent for MRI containing a complex between a polyanionic gadolinium (Gd)-based contrast agent and a cationic polymer, or a complex between a polycationic Gd-based contrast agent and an anionic polymer; these complexes are able to form a polyion complex, wherein the contrast agent can produce MRI contrast only in the presence of polyelectrolyte in the neutral pH range.
Further, Patent Document 2 discloses a contrast agent comprising a complex between a gadolinium (Gd)-based contrast agent and a polymer, wherein the polymer undergoes a phase change in response to environmental changes, and thereby changes the water solubility.
Another Gd complex, as shown in FIG. 1, has also been reported. This Gd complex is formed by coordination of a dendrimer to Gd3+, the dendrimer being formed by the reaction of DTPA or DOTA with NH3+ groups at the terminals of polyamidoamine (PAMAM) dendrimer.
However, a metal complex having DTPA or DOTA as the chelating ligand has low contrast performance. In other words, the sensitivity to detect target cells such as tumors and the like is low. Accordingly, when a contrast agent that contains the above-described complex as the essential component is used, the concentration of the complex in the contrast agent must be high. Such a high concentration of the contrast agent poses a problem, i.e., the risk of adverse effects with the use of the contract agent is high.
Further, there is a demand for an MRI diagnosis that can be performed in the future using a high magnetic field, in order to obtain a higher resolution. However, the contrast performance of the above-mentioned metal complexes is reduced in high magnetic fields, thus making it difficult to use them for MRI diagnosis in a high magnetic field. Further, because the molecular weights of DTPA and DOTA are low, the complexes tend to diffuse in the body, thus causing images to become blurred easily. In other words, the use of a complex between DTPA or DOTA and Gd poses problematically low resolution in diagnostic images.
Further, the use of Gd complex to which DTPA or DOTA is coordinated tends to cause Gd3+ to be dissociated from the complex. Accordingly, a contrast agent that uses the complex is highly toxic.
Further, the Gd complex is highly mobile (molecular rotation easily occurs). This can reduce the contrast performance.
Note that, although the Gd complex shown in FIG. 1 is excellent in terms of the contrast performance and the like, it is difficult to synthesize.
[Patent Document 1] WO98/41241
[Patent Document 2] Japanese Unexamined Patent Publication No. 2000-86538